Celiac disease is a common (frequency of 1%) immune-mediated disease associated with significant morbidity and mortality. Results of a GWAS of celiac disease from the UK and two follow-up studies in European and North American celiac cases and controls of the top 1020 most associated SNPs have been reported. The combined results of the GWAS and two follow-up studies showed strong evidence for celiac disease loci in six chromosomal regions at 1q31, 2q31, 3q25, 3q28, 4q27 and 12q24. The two most significantly associated regions are a 482 kb region on 4q27 harboring the IL2 and IL21 genes, and a 52 kb region on 3q21 harboring the LPP gene. Many of the common SNPs in the regions show highly significant associations with disease (pvalues <1[unreadable]10-9), but none of them appear to be causal. In this proposal, we will identify all the genetic variation within these six celiac disease regions, assess the potential of each locus to affect the disease, and then measure the statistical evidence for disease involvement for each of the putative disease loci. We will capitalize on existing North American resources, including a large collection of celiac disease probands and their families, and an independent set of celiac cases and controls. For Aim 1, we will perform fine resolution mapping in the six replicated regions in order to identify the boundaries of each region for deep sequencing in Aim 2. For Aim 2, we will identify genetic variation in the approximately 950 kb of sequence in the six regions in 232 celiac disease probands and 248 independent unaffected controls through deep sequencing using the Illumina Genome Analyzer II sequencing system. We will then select a set of variants that are most likely to be directly related to disease. For Aim 3, we will genotype150 of the variants identified in Aim 2 in 1500 affected and unaffected family members of the 232 probands, assess segregation of the alleles with disease, and estimate penetrance. For Aim 4, we will further investigate the 150 putative celiac disease alleles in 2455 celiac disease cases and 2110 unaffected controls from North America. Evidence for disease involvement will be based on statistical evidence, the predicted function of the putative disease alleles, and the segregation observed in the families. At the conclusion of this study, we will have characterized the genetic variation within the strongest celiac disease regions and measured the statistical evidence supporting the involvement of each variant in the disease. Functional studies will then need to be done to determine causality. Identifying the genetic causes of celiac disease will allow us to identify susceptible individuals and advance new ways of preventing and treating celiac disease, as well as gain more understanding of associated auto-immune and inflammatory diseases. The data and results will be shared with the scientific community.